Each year, over 1.7 million Americans sustain traumatic brain injury (TBI) of which 75% represent concussion and other forms of mild closed head injury. In addition, about 15% of military Service Members suffer mild TBI each year, most commonly from exposure to improvised explosive devices (IEDs). The CENC VA TBI BTR, Boston VA will work in collaboration with the CENC BTR, Uniformed Services University of the Health Sciences (USUHS) to establish the CENC VA TBI Brain Donation Registry and CENC VA TBI Brain Tissue Repository at VA Boston with the purpose of understanding the effects of military- related blast and concussive TBI in Veterans by conducting state-of-the-art diagnostic neuropathological evaluation on Veteran brain donors with a history of TBI. Clinical assessments will either by done with the donor antemortem via the phone or in postmortem phone interview with the donor's family. We estimate that we will enroll at least 50 (approximately half at VABHS) new veterans per year nationally in the antemortem study. We estimate that post-mortem cases could contribute another 25 cases a year, and this will be important to provide researchers with material immediately. Regardless of the rate of brain donation, the amount of TBI-specific clinical information collected by the CENC VA TBI Brain Donation Registry will produce a rich research database that will be available to investigators. The PIs of the CENC BTR Boston VA and the CENC BTR, USUHS, along with CENC leadership, will hold monthly conference calls to review and discuss CENC BTR efforts, including recruitment, specimen quality, handling, diagnostic procedures, results and coordination of joint research efforts. In addition, CENC BTR PIs and relevant staff will hold quarterly face-to-face meetings to jointly review cases and discuss other CENC BTR issues. Secondly, the CENC VA TBI BTR will work to identify unique molecular pathological signatures associated with military-related blast and concussive TBI and neurodegeneration, including Chronic Traumatic Encephalopathy (CTE) and Alzheimer's disease (AD). Our guiding hypothesis is that acute TBI produces biomechanical shearing forces that selectively injure axons, small blood vessels and astrocytes. After TBI, the microtubule-associated protein, tau, becomes dissociated from microtubules and abnormally phosphorylated, misfolded, cleaved and aggregated; all of which promote neurotoxicity. With repetitive TBI, these neurotoxic aggregates of tau accumulate and overwhelm normal clearance mechanisms, allowing tau to spread interneuronally and transynaptically, as well as via astrocyte-to- astrocyte transmission and extracellular cerebrospinal fluid clearance pathways. Acute TBI disrupts the microvasculature and astrocytic end feet damaging the blood brain barrier. The disruption of the blood brain barrier educes an inflammatory cascade that further exacerbates axonopathy, the aggregation and spread of toxic tau protein, and neurodegeneration. Furthermore, in susceptible individuals, progressive axonopathy and toxic tau aggregates provoke the deposition of other proteins associated with neurodegenerative disease, including amyloid-, alpha-synuclein and TDP-43. CENC will be to distribute CNS tissue to qualified VA and DoD investigators studying military-related blast and concussive TBI and related disorders and (e) communicate.